Signaling pathway for aloe‐emodin‐induced apoptosis in human H460 lung nonsmall carcinoma cell

Abstract

Aloe-emodin (1,8-dihydroxy-3-(hydroxymethyl)-anthraquinone) is an active component from the root and rhizome of Rheum palmatum that has been reported to exhibit antitumor effects through an unknown mechanism. Our study investigated the mechanisms of aloe-emodin-induced cell death in the human lung nonsmall cell carcinoma cell line H460. Aloe-emodin (40 M)-induced apoptosis of H460 cells involves modulation of cAMP-dependent protein kinase, protein kinase C, Bcl-2, caspase-3 and p38 protein expression. Rheum palmatum L. has been used in Chinese medicine for a long time. Previous treatments of diseases with herbs were empirical more than theoretical. Therefore, clarifying the mechanisms of action of the components of herbs may be important for developing their applications. Aloe-emodin, an active component of the root and rhizome of Rheum palmatum L., 1 has been demonstrated to possess anti-tumor activity. [2][3][4] The mechanisms of the aloeemodin-produced anticancer effects, however, remain unknown. The present study served to investigate the mechanisms of aloeemodin-induced apoptosis on human nonsmall cell lung carcinoma cell H460.Apoptosis is a major form of cell death, which involves many factors such as expression and translocation of Bcl-2 family proteins, activation of caspases, expression of protein kinase C (PKC) family, cAMP-dependent protein kinase (PKA) and mitogen-activated protein kinase (MAP kinase) members signal transduction pathways. The Bcl-2 family proteins, such as Bcl-2, Bcl-X L , Bak and Bax, are the best-characterized regulators of apoptosis. 4,5 Caspases, a family of cysteine proteases, play a critical role during apoptosis. There are at least two major mechanisms (one involving caspase-8 and the other involving caspase-9) 6,7 that directly or indirectly activate "effector" caspases such as caspase-3. 8,9 Many investigators have reported that activation of cAMP signaling is involved in apoptosis. 10,11 The role of cAMP in various cell responses is mediated by the cAMP-dependent protein kinase. The dissociation, however, of catalytic subunit from inactive PKA is the marker of the activity of PKA. The present study determined the change of PKAc (PKA catalytic subunit) in aloe-emodininduced apoptosis. PKC represents 11 isozymes that have been implicated in the regulation of apoptosis. 12,13 The contribution of individual PKC isozymes to this process, however, is not well understood. Many reports suggested that the degradation of ␦PKC was directly concerned in apoptosis in all of the PKC isozymes. 13,14 The relationship between activation of caspase and ␦PKC was investigated in many reports. These reports suggest that ␦PKC should lie upstream or downstream of caspase-3. 13,14 We examined the changes of ␦PKC and caspase-3 and the specificity of the PKC-caspase-3 relationship on aloe-emodin-induced apoptosis.The mitogen-activated protein kinase (MAP kinase) members can be grouped into 3 major classes: the extracellular signalregulated protein kinases (ERKs), the c-jun N-terminal kinases (JNKs) ...

Emodin ameliorates high-glucose induced mesangial p38 over-activation and hypocontractility via activation of PPARγ

“…Emodin at 50 mg/l and 100 mg/l reduced p-p38 levels by 40% and 73%, respectively. This finding is consistent with other in-vitro studies using human umbilical vein endothelial cells (Kwak et al, 2006), human lung non-small cell carcinoma cells (Yeh et al, 2003), and retina ganglion cells (Lin et al, 2007) in which the pharmacological effect of emodin was mediated via inhibition of p38. Our previous study also demonstrated that emodin normalizes IL-1β induced mesangial cell p38 over-activation (Wang et al, 2007).…”

The Role of Salicylic Acid in the Induction of Cell Death in Arabidopsis acd11

“…While phylloquinone has no apoptosis-inducing activity in animal cells, such activity has been found for both the related menaquinone (vitamin K2) and several anthraquinones (Miyazawa et al, 2001;Lin et al, 2003;Yeh al., 2003). The synthetic, water-soluble menadione (vitamin K3) is also a potent inducer of PCD in tobacco protoplasts (Sun et al, 1999), and menadione bisulphite induces rapid and extensive leaf necrosis when sprayed onto Arabidopsis plants at 1 to 3 mM concentration (P. Brodersen and F.G. Malinovsky, unpublished data).…”

Formulation, antileukemia mechanism, pharmacokinetics, and biodistribution of a novel liposomal emodin

“…Downregulated Bcl-2 along with unaffected Bax was found in human H460 non-small-cell lung cancer cell lines. 2 Upregulation of the Bax/Bcl-2 ratio was reported in human neuroblastoma cell lines SJ-N-KP 23 and human lung squamous carcinoma cell line CH27. 22 Emodin decreased Mcl-1, but did not significantly affect the expressions of Bcl-2 and Bax proteins in myeloma cells, such as U266, IM-9, KMS-12-PE, RPMI8226, 1 and HL-60, 24 have also been reported.…”

“…(Figure 1). Emodin shows a wide variety of pharmacological activities such as anticancer, [1][2][3][4] antifibrosis, [5][6][7] antirestenosis, 8,9 and antimicrobial activities. 10 However, emodin is poorly soluble in water, which limits its applications in vivo.…”